Abi pathway in Breast Cancer Metastasis

乳腺癌转移中的 Abi 通路

基本信息

批准号：
7586418
负责人：
ZONGHAN DAI
金额：
$ 16.34万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7586418
关键词：
Accounting Actins Adhesions Animal Model Arts Behavior Biological Markers Brain Breast Cancer Cell Cancer Cell Growth Cancer Patient Cancer cell line Cell Adhesion Cell physiology Classification Clinical Clinical Management Complex Cytoskeleton Data Development Diagnosis Disease Progression Distant Early Diagnosis Female Gene Silencing Human In Vitro Intervention Leukemic Cell Liver Lung Malignant Neoplasms Mediating Molecular Names Neoplasm Metastasis Pathway interactions Patients Phenotype Phosphorylation Play Principal Investigator Prognostic Marker Protein Family Protein Tyrosine Kinase Proteins Proteomics Regulation Research Role Signal Pathway Signal Transduction Site Specimen Staging Structure Techniques Testing Therapeutic Tumor Cell Invasion United States Woman base bone breast cancer diagnosis cell motility cohort design genetic regulatory protein improved in vivo leukemogenesis lymph nodes malignant breast neoplasm metastatic process migration mouse model neoplastic cell novel outcome forecast polymerization prognostic programs public health relevance small hairpin RNA treatment strategy tumor growth

项目摘要

DESCRIPTION (provided by applicant): ): The overall objective of the proposed research is to delineate the mechanisms that regulate motility and invasive behavior of breast cancer cells. The proposal is based on a hypothesis that the components in the regulatory machinery of actin cytoskeleton organization play a critical role in breast cancer metastasis. These regulatory proteins may be used as the biomarkers for diagnosis and/or prognosis of metastatic breast cancer. Specifically, we postulate that the signaling pathway mediated by Abl interactor (Abi) proteins may play a key role in breast cancer metastasis, as this pathway is crucial for control of actin polymerization. To test this hypothesis, we will examine the expression, phosphorylation, complex formation, and subcellular localization of the proteins involved in Abi signaling in breast cancer cell lines as well as in paired specimens isolated from patients with breast cancer. A pathway-specific proteomic approach is designed to identify the components of Abi signaling that are abnormally expressed and/or modified in metastatic breast cancer cells. The role of Abi pathway in breast cancer metastasis will be tested by approaches using small hairpin RNA-mediated gene silencing and animal model. We anticipate that these approaches may yield critical data that will establish the clinical utility of the Abi pathway as a biomarker and target for metastatic breast cancer diagnosis and intervention. Understanding how the breast cancer cells escape the normal control of cell motility and become metastatic will help the development of new prognostic and therapeutic strategies for treatment of human breast cancer PUBLIC HEALTH RELEVANCE Breast cancer is the most common cancer in women in the United States and accounts for about 25% of all female malignancies worldwide. The lethality of breast cancer is largely due to the metastasis of the tumor cells to distant sites including lymph nodes, bone, liver, brain, and lung. A major challenge in clinical management of breast cancer has been to improve the ability to detect metastatic development at the early stage. The proposed research is aimed at the improving our understanding of the molecular mechanisms of the metastatic process of breast cancer and developing novel prognostic markers for early detection of metastatic breast cancer. The research focuses on a complex of molecules critical for regulation of fundamental cellular process required for cell migration and invasion. The state-of-art techniques will be employed to identify novel diagnosis and prognosis markers. These novel biomarkers will be tested in a cohort of breast cancer patients to determine their clinical utility. Furthermore, the role of these molecules in development of breast cancer metastasis will be tested in an animal model. Understanding how the breast cancer cells escape the normal control of cell motility and become metastatic will help the development of new prognostic and therapeutic strategies for treatment of human breast cancer

描述（由申请人提供）：）：拟议研究的总体目标是描述调节乳腺癌细胞运动和侵袭行为的机制。该提议基于这样的假设：肌动蛋白细胞骨架组织的调节机制中的成分在乳腺癌转移中发挥着关键作用。这些调节蛋白可用作转移性乳腺癌的诊断和/或预后的生物标志物。具体来说，我们假设 Abl 相互作用蛋白 (Abi) 介导的信号通路可能在乳腺癌转移中发挥关键作用，因为该通路对于控制肌动蛋白聚合至关重要。为了检验这一假设，我们将检查乳腺癌细胞系以及从乳腺癌患者分离的配对样本中参与 Abi 信号传导的蛋白质的表达、磷酸化、复合物形成和亚细胞定位。通路特异性蛋白质组学方法旨在识别转移性乳腺癌细胞中异常表达和/或修饰的 Abi 信号传导成分。 Abi 通路在乳腺癌转移中的作用将通过使用小发夹 RNA 介导的基因沉默和动物模型的方法进行测试。我们预计这些方法可能会产生关键数据，从而确定 Abi 通路作为转移性乳腺癌诊断和干预的生物标志物和靶标的临床效用。了解乳腺癌细胞如何逃脱细胞运动的正常控制并发生转移，将有助于开发治疗人类乳腺癌的新预后和治疗策略公共卫生相关性乳腺癌是美国女性最常见的癌症，据统计约占全球所有女性恶性肿瘤的 25%。乳腺癌的致死率很大程度上是由于肿瘤细胞转移到远处部位，包括淋巴结、骨、肝、脑和肺。乳腺癌临床管理的一个主要挑战是提高早期检测转移发展的能力。拟议的研究旨在提高我们对乳腺癌转移过程的分子机制的理解，并开发用于早期检测转移性乳腺癌的新型预后标志物。该研究重点关注对调节细胞迁移和侵袭所需的基本细胞过程至关重要的分子复合物。最先进的技术将用于识别新的诊断和预后标志物。这些新型生物标志物将在一组乳腺癌患者中进行测试，以确定其临床效用。此外，这些分子在乳腺癌转移发展中的作用将在动物模型中进行测试。了解乳腺癌细胞如何逃脱细胞运动的正常控制并发生转移将有助于开发人类乳腺癌的新预后和治疗策略